Time Stamps

• 00:48 Background on Beta Blockers and Their Mechanism
• 02:41 Historical Context of Beta Blockers in Heart Disease
• 04:56 Capricorn Trial and Its Impact
• 07:17 Emergence of Doubts About Beta Blockers
• 10:09 Introduction to the REDUCED-AMI Trial
• 15:52 Discussion on Trial Interpretation and Clinical Implications
• 16:18 Comparison with Other Trials and Future Directions

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Show Notes

Background

• Beta blockers decrease myocardial oxygen demand by reducing:
  • Heart rate
  • Blood pressure
  • Myocardial contractility
• Trials that established the clinical benefit of beta blockers in patients with left ventricular ejection fraction (LVEF) <40% and stabilized HF:
  • CIBIS-II – Bisoprolol in HFrEF
  • MERIT-HF – Metoprolol succinate in HFrEF
  • COPERNICUS – Carvedilol in HFrEF
• • NOTE: These trials were conducted in the pre-reperfusion, pre-P2Y12 inhibitor era

Guidelines

• 2025 ACC/AHA Guideline: early initiation of oral beta-blocker therapy post-MI to reduce the risk of arrhythmias and reinfarction for the management of patients with acute coronary (Class IA indication).
  • NOTE: Long-term benefit from continued use after hospital discharge remains unclear in patients with preserved LVEF!
• 2023 ESC Guideline:prescribing beta-blockers after uncomplicated ACS in patients with LVEF >40% is less well established.

Evolution and mechanism of action of beta-blockers

• Types of beta‐blockers:
  • Non‐selective beta‐blockers
  • Selective beta‐blockers
• Beta₁‐receptor
  • Location:
    • Heart
      • Positive chronotropic effects (increases heart rate)
      • Positive inotropic effects (increases contractility of the myocardium)
    • Kidney
      • Increased release of renin, which in turn increases blood pressure
• Beta₂‐receptor
  • Location:
    • Smooth muscle cells
      • Promotes relaxation
    • Skeletal muscle cells
      • Promotes tremor and increased glycogenolysis
    • Liver
      • Increases glycogenolysis
• Beta₃‐receptor
  • Location:
    • Adipose tissue
      • Induces lipolysis
• Administration: intravenous and oral
• First‐generation non‐selective beta‐blockers
  • Affect all beta‐receptors.
  • (e.g. propranolol, oxprenolol, sotalol, timolol)
• Second‐generation selective beta‐blockers
  • Mainly affect the heart
  • e.g. metoprolol, bisoprolol, acebutolol, atenolol, esmolol
• Third‐generation beta‐blockers, combined non‐selective beta‐blocking effects and alpha‐blocking effects (e.g. carvedilol)
  • Affect all beta‐receptors plus alpha‐receptors in the vessels, lowering blood pressure
  • e.g. carvedilol

Beta blockers following an MI by decade

• • 1980s
    • Beta-Blocker Heart Attack Trial or BHAT (1982)
      • Multicenter, randomized, double-blind, placebo-controlled trial
      • Evaluated the effect of propranolol on mortality in patients who had survived an acute myocardial infarction
        • Population: 3,837 patients within 5–21 days after myocardial infarction
        • Randomization: propranolol (180–240 mg/day in divided doses) or placebo
          • Maintenance dose was determined based on serum drug levels
        • Primary endpoint: total mortality during an average follow-up of 27 months
        • Outcome: Propranolol significantly reduced total mortality compared to placebo
          • Greatest benefit observed in patients at higher risk, such as those with persistent ST-segment depression on ECG after infarction
        • Clinical impact: Established long-term beta-blocker therapy as a standard of care for secondary prevention after myocardial infarction, especially in high-risk subgroups
  • 1990s
    • CAPRICORN (Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction) trial (2001)
      • Multicenter, randomized, double-blind, placebo-controlled study
      • Evaluated carvedilol in patients with left ventricular ejection fraction (LVEF) ≤40% after acute myocardial infarction (MI)
        • Population: 1,959 patients were enrolled 3–21 days post-MI, all clinically stable and already receiving standard post-MI therapy, including ACE inhibitors, aspirin, and statins
          • Approximately half had clinical heart failure at baseline.
        • Randomization: carvedilol (starting at 6.25 mg twice daily, titrated as tolerated to a maximum of 25 mg twice daily) or placebo, with a mean follow-up of 1.3 years.
        • Outcome (Primary): All-cause mortality was significantly reduced in the carvedilol group (11.9%) compared to placebo (15.3%)
          • Hazard ratio 0.77 (95% CI 0.60–0.98, p=0.03)
          • Relative risk reduction: 23%
        • Outcome (Secondary): Carvedilol also reduced cardiovascular mortality, recurrent nonfatal MI, and the composite of all-cause mortality or nonfatal MI
        • Clinical Impact: carvedilol provides additional mortality and morbidity benefit in post-MI patients with LV dysfunction, on top of contemporary standard-of-care therapies
  • 2000s
    • Advent of modern therapies!
      • Anti-platelet agents
      • Statins
      • Percutaneous coronary interventions
    • This led to a re-evaluation of the role of beta blockers!
      • Questions arose regarding their efficacy in stable ischemic heart disease (IHD) without recent MI or heart failure.
  • 2010s
    • Meta-analysis (2015)
    • Population: 10 observational studies with a total of 40,873 patients who had acute myocardial infarction (AMI) and underwent percutaneous coronary intervention (PCI)
    • Results:
      • Oral beta-blocker use after PCI for AMI was associated with a significant reduction in all-cause mortality
        • Adjusted hazard ratio 0.76, 95% CI 0.62–0.94
      • The survival benefit of beta-blockers was significant within the first year of follow-up, but not consistently observed beyond one year.
      • The mortality benefit was most pronounced in patients with
        • Reduced ejection fraction
        • Lower use of other secondary prevention drugs
        • Non-ST-segment elevation myocardial infarction (NSTEMI)
      • There was no significant mortality benefit or reduction in cardiac death, recurrent myocardial infarction, or heart failure readmission with oral beta-blocker therapy for patients with preserved LVEF after acute myocardial infarction treated with percutaneous coronary intervention.
  • 2021 Cochrane systematic review
    • in patients who have had a myocardial infarction but do not have heart failure (and with LVEF >40%):
      • Beta-blockers probably reduce the risks of all-cause mortality and myocardial reinfarction compared with placebo or no intervention
        • However, the evidence base is limited by high risk of bias from trials from the pre-reperfusion era and lack of modern-era trials.

REDUCE-AMI, NEJM, 2024

REDUCE-AMI

• • Study Design: Registry-based, prospective, open-label, parallel-group, randomized clinical trial
    • Three countries: Sweden (38 centers), Estonia (1 center), and New Zealand (6 centers)
  • Population: Sept 2017-May 2023
    • 5020 patients were enrolled;
      • 2508 were assigned to beta blockade
      • 2512 to non beta blockade.
  • The median age of the patients was 65 years, 22.5% of the patients were women, and 35.2% had an ST-segment elevation myocardial infarction.
  • Methods:
    • Inclusion criteria:
      • Men or women age ≥18 at the time of signing the informed consent
      • Day 1-7 after type 1 MI(either ST elevation MI or non-ST-elevation MI)
        • According to the fourth universal definition of MI
      • Coronary angiography performed during hospitalization.
      • Obstructive coronary artery disease documented by coronary angiography,
        • Stenosis ≥50 %
        • FFR ≤0.80 or
        • iFR ≤0.89 in any segment at any time point before randomization.
      • Echocardiography performed after the MI showing a preserved ejection fraction defined as EF≥50%.
    • Exclusion criteria:
      • Any condition that may influence the patient’s ability to comply with study protocol
      • Contraindications for beta-blockade
      • Indication for beta-blockade other than as secondary prevention according to the treating physician
    • Randomization: 1:1 according to trial center
      • Assigned by a Web-based system
      • Beta-blocker group:
        • Metoprolol (first choice) or bisoprolol (alternative) during the remaining hospital stay and received a prescription for continued use after discharge.
          • Encouraged to aim for metoprolol dose of at least 100mg or bisoprolol dose of at least 5mg
• Primary endpoint:
  • Composite of death from any cause or new myocardial infarction
• Secondary endpoints:
  • death from any cause
  • death from cardiovascular causes
  • myocardial infarction
  • hospitalization for atrial fibrillation
  • hospitalization for heart failure
• Results:
  
  • Population:
    • • Median age: 65 years
      • 22.5% of the patients were women
      • 35.2% had an ST-segment elevation myocardial infarction
    • Beta-blocker group: 2508 patients w
      • 1560 (62.2%) treated with metoprolol
      • 948 (37.8%) treated with bisoprolol
    • Median follow-up: 3.5 years (interquartile range, 2.2 to 4.7) in each trial group.
  • Primary:
    • Death from any cause or a new myocardial infarction:
      • 199 of 2508 patients (7.9%) in the beta-blocker group
      • 208 of 2512 patients (8.3%) in the no–beta-blocker group
      • hazard ratio, 0.96; 95% confidence interval, 0.79 to 1.16; P=0.64
  • Secondary:
    • Beta-blocker treatment did not appear to lead to a lower cumulative incidence of the secondary end points of:
      • death from any cause
      • death from cardiovascular causes
      • myocardial infarction
      • hospitalization for atrial fibrillation
      • hospitalization for heart failure

ABYSS, NEJM, 2024

• Study Design: multicenter, open label, randomized, noninferiority trial
  • Conducted at 49 sites in France
• Randomization: patients with a history of myocardial infarction, in a 1:1 ratio
  • Interruption or continuation of beta-blocker treatment
• Follow up: Median of 3 years
• Outcomes:
  • Interruption of long-term beta-blocker therapy was NOT noninferior to continuation for the composite outcome of:
    • death
    • nonfatal MI
    • nonfatal stroke
    • cardiovascular hospitalization The risk difference for the primary outcome was 2.8 percentage points (95% CI, <0.1 to 5.5), failing to meet the pre specified noninferiority margin of 3%
  • No improvement in quality of life with beta-blocker interruption Nnumerical increase in recurrent angina and coronary-related hospitalizations was observed in the interruption group,
    • Though these were not formally tested for significance.

Conclusions/Takeaways

• Beta blockers remain a mainstay of management for patients with reduced ejection fraction following myocardial infarction and in patients with chronic systolic heart failure and no prior myocardial infarction.
• In patients with preserved left ventricular function after an uncomplicated myocardial infarction, the benefit of beta blockers is uncertain and should not be assumed based on older trials.
• Longstanding clinical practices should be periodically re-evaluated in light of changes in the standard of care.
  • Most evidence should have an expiration date.
    • Just because something has been standard for decades does not mean it remains the best approach today.
• Historical studies supporting beta blockers after myocardial infarction were conducted in the pre-reperfusion era and may not apply to all patients treated with contemporary revascularization, lipid lowering , and antithrombotic therapies.
• REDUCE-AMI found no benefit from routine beta blocker initiation in post-MI patients with preserved ejection fraction, challenging a longstanding default approach in cardiology.

Other resources:

• NEJM Editorial for REDUCE-AMI: “Routine Beta-Blockers in Secondary Prevention — On Injured Reserve” https://www.nejm.org/doi/full/10.1056/NEJMe2402731
• NEJM Editorial for Abyss: “Routine Beta-Blockers in Secondary Prevention — Approaching Retirement?” https://www.nejm.org/doi/full/10.1056/NEJMe2409646
• NEJM Clinical Decisions: “Beta-Blocker Therapy after Acute Myocardial Infarction — To Block or Not to Block?” https://www.nejm.org/doi/full/10.1056/NEJMclde2410735

Transcript

Dr. Greg Katz: Welcome to another episode of Beyond Journal Club, a collaboration between CORE IM and NEJM Group.

Dr. Shreya Trivedi: The goal of Beyond Journal Club is to take landmark clinical trials and put them into context, telling the story of how we got to where we are and what it means for how we take care of our patients. I am Dr. Shreya Trivedi, an internist at BIDMC.

Dr. Greg Katz: I am Dr Greg Katz, a Cardiologist at NYU.

Dr. Chris Kotanidis: I’m Dr. Chris Kotanidis, an Editorial Fellow at the New England Journal of Medicine.

Dr. Clem Lee: And I’m Dr. Clem Lee, former fellow and a current guest editor at the New England Journal of Medicine.

Dr. Chris Kotanidis: Today we’ll be discussing the REDUCE-AMI trial. This trial explored the role of beta-blockers in patients with a recent heart attack.

Dr. Greg Katz: This is one of those studies that makes me think of the old adage they tell you when you start med school – in 10 years, half of what you learn is going to be wrong? The problem is that we don’t know now which half it is.

Dr. Clem Lee: I’m so excited to get into this, because for at least as long as I can remember, beta blockers have been considered the standard treatment after a heart attack.

Dr. Chris Kotanidis: Before we spoil any conclusions. First we’re going to talk about why beta blockers even make sense, as opposed to my treatment in the first place. Then we’ll get into the story of beta blockers and how their indications might have evolved over time.

Dr. Shreya Trivedi: And finally, we’ll take a deep dive into the REDUCE-AMI trial and think about whether some of the textbook ideas we learned about in medical school may have passed that clinical expiration date.

Mechanism of Beta-Blockers

Dr. Chris Kotanidis: All right. To kick off a story of beta blockers, AMI, we first need to dive into how beta blockers work in the first place. Why do we think that beta blockers could even help with mis to begin with?

Dr. Clem Lee: Well, beta receptors are located all over the body, but we’re going to focus our discussion today on the heart. So that means we’ll stay cardioselective with beta one receptors, which are predominantly located on the myocardium.

Dr. Chris Kotanidis: So, beta one receptor is responsive to changes in sympathetic and vagal tone. And so when these are stimulated with drugs like norepinephrine or epinephrine, heart rate goes up and contractility increases. When you block them, like with the beta blocker, a heart rate slows down and the heart contracts less force.

Dr. Shreya Trivedi: Yes. And so then after a heart attack, the thinking is that by decreasing the heart rate and contractility, you also lower the myocardial oxygen demand. And so in the situation where the myocardium isn’t getting enough blood flow, like in a heart attack, Beta Blockers can help reduce damage to the heart.

Dr. Chris Kotanidis: Exactly. But beta blockers don’t just decrease heart rate. They also reduce the risk of arrhythmias.

Dr. Greg Katz: And as we’re talking here, I think it’s worth pointing out that there is a difference between treating somebody during an acute MI with a beta blocker, which has a lot of risk, versus treating somebody after an MI that’s been revascularized. And so for the purpose of our discussion, we’re really talking about treating patients after an MI when they’ve been treated and stabilized.

Dr. Clem Lee: I look forward to that conversation, Craig, but for now, we’ve laid the foundation for beta blocker physiology, and so let’s look at how these drugs went from theoretically beneficial to being the standard of care.

Beta-Blockers in Ischemic Heart Disease by Decade

1960s-1970s: The Early Years

Dr. Chris Kotanidis: Okay, so the story with beta blockers and ischemic heart disease starts in the 1960s and 70s. Back then, we had some small studies that showed a reduction in mortality and reinfarction in patients who had an MI.

Dr. Greg Katz: But those trials weren’t big enough to fully change practice. Beta blockers fully rose to prominence after the landmark beta blocker heart attack trial published in 1982 in JAMA.

Dr. Shreya Trivedi: and this trial is written now as B, H, A, T, beta blockers and heart attack trial, and we went back and forth. Is it bot? Is it B-HAT? If anyone knows how to actually pronounce it, please email us. But for, I guess, the sake of the rest of this episode, we’re just gonna call it B-HAT

Dr. Clem Lee: Yeah, that’s I’m cool with that. So B-HAT showed us that patients treated with propranolol after a heart attack were less likely to die than those treated with placebo.

Dr. Chris Kotanidis: And B-HAT also had a really interesting study design. So the investigators here actually titrated up the dose of propranolol until they got to the serum level they wanted patients to achieve.

Dr. Greg Katz: Testing serum levels and adjusting doses In 1982? This is like the OG precision medicine paper.

Dr. Chris Kotanidis: Yeah yeah, I know, right, and the results are kind of unimpeachable. Propranolol reduced mortality, cardiac death and arrhythmic death compared to placebo.

Dr. Shreya Trivedi: Ah so cool to see a trial take a theoretical mechanism action of lowering oxygen demand, and that actually ends up predicting the results of better outcomes from beta blockers entirely.

Dr. Greg Katz: So B-HAT was a game changer and establish beta blockers as the standard of care in ischemic heart disease after an MI. I mean, what’s not to love? They reduce death, treat angina, reduce arrhythmias. And we can’t forget how revolutionary this was. At the time when Behat was published, we didn’t have anything like the arsenal of heart attack treatments that we do today. No statins, no PCI, no p2 i 12 inhibitors. Even bypass surgery was just coming onto the scene, so at this point in time, if you had a heart attack, all you did was like, get put in the corner, take morphine and try not to die.

Dr. Shreya Trivedi: Gotta love this!

Dr. Chris Kotanidis: Yeah, well after B-HAT, the momentum for beta blockers has continued with the CAPRICORN trial, which stands for the very easy Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction, which was published in 2001 in the Lancet.

Dr. Clem Lee: Oh. That full trial name is a mouthful, so I’m glad they abbreviated it. CAPRICORN came on the heels of major heart failure trials showing the efficacy of beta blockers. So there was a lot of palpable excitement for beta blockers in general.

Dr. Greg Katz: So CAPRICORN was different from B-HAT in two ways. CAPRICORN looked at 1) sicker patient population post MI who also had LV dysfunction and (2) these patients were on better medical therapy. We had ACE inhibitors, a lot of them for PCI, thrombolytics. These were just sicker patients who had better medical therapy when they were enrolled in this study.

Dr. Shreya Trivedi: Yeah. And what did CAPRICORN show? CAPRICORN showed a large mortality benefit in post MI with a reduced ejection fractions and that really cemented beta blockers as a mainstay treatment in patients with Left Ventricular Systolic Dysfunction post-MI.

Dr. Greg Katz: One of the things that’s really interesting about CAPRICORN is that there are a number of different plausible explanations for why Carvedilol was so successful in this study. One is it’s just a beta blocker, and beta blockers help in ischemic heart disease and systolic heart failure.

Dr. Greg Katz: And then the second hypothesis is maybe there’s something special about Carvedilol. Maybe it’s the Alpha blockade that has increased afterward reduction. Maybe it’s the antioxidant effects, the metabolic effects, where Carvedilol tends to improve insulin sensitivity and other beta blockers tend to make it worse.

Dr. Chris Kotanidis: Yeah. So just to reiterate what we’ve talked about so far, CAPRICORN solidified beta blockers after an MI with a reduced ejection fraction, and so the standard of care was born.

Dr. Shreya Trivedi: Yes, but where do we go from here? How did we get to the point where the beta blocker plot thickened enough for us to even question beta blockers, right? What was the setup for the REDUCE-AMI trial?

The Plot Thickens

Dr. Clem Lee: All right. So actually, Shreya, it took a while for that plot to thicken, decades even. It was so striking to me just how long that gap was between the major trials in this space. So if you look at the B-HAT that was in 1982 and their protocol was almost like handwritten, if you look at it, and then CAPRICORN, MERIT HF, and CIBIS II were all published by 2001 and then there were no other big RCTs looking at beta blockers and patients post MI, until now, REDUCE-AMI.

Dr. Shreya Trivedi: But obviously there was still some great stuff going on in the background. You know, we had all these advanced lipid management, PCIs, antiplatelet therapy. There was this whole revolution in the way we take care of patients with diabetes and cardiovascular disease. So basically, the way we take care of stable ischemic heart disease completely changed in those couple of decades.

Dr. Greg Katz: And over that time, the narrative on beta blockers for ischemic heart disease just started changing a little bit. There were a handful of important observational papers that started looking at the role of beta blockers in patients who had stable ischemic heart disease, but didn’t have systolic heart failure, and really started questioning whether they truly had a benefit.

Dr. Chris Kotanidis: That’s right, Greg, it was interesting to me to dig into the evidence here, and I realized a pattern started to emerge. A lot of these observational studies suggested an upfront benefit of beta blockers in the first 30 Days to a year, but after that, the benefit really seemed to subside.

Dr. Shreya P. Trivedi: Yeah, and to suit that point a little bit more, there was a 2015, meta analysis involving over 40,000 patients posted by that showed beta blockers did improve the survival overall, but in the subgroup analysis, its benefit waned after 1 year of beta blocker therapy and didn’t show a survival benefit in patients with a preserved ejection fraction, so that evidence started to call into question, hey, is there a benefit in patients with preserved ejection fraction? And how long should we keep patients on beta blockers post MI?

Dr. Clem Lee: And then in 2016 the FAST-MI registry study showed a very similar pattern that early beta blocker therapy was associated with reduced short term mortality, but not reduced one year mortality

Dr. Greg Katz: And it was just meta analysis after meta analysis, including one that had over 100,000 patients, that continued to suggest little to no benefit of beta blockers in patients post MI who didn’t have heart failure. And some of the registry data even called into question whether there was a short term benefit of that first year of beta blockers post MI.

Dr. Shreya Trivedi: Ah wow, this is getting super juicy. No benefit at all. Wow.

Dr. Chris Kotanidis: I know, right. It’s a big contrast to the earlier decades, isn’t it? And by the end of the 2010s clinical guidelines had begun to reflect this uncertainty.

Dr. Shreya P. Trivedi: Yeah. So the body of evidence really brought us to this important question: do beta blockers still belong among the contemporary therapies for ischemic heart disease?

Dr. Greg Katz: And all of this data, which even includes a Cochrane review on the topic in 2021 really made the compelling case that another trial seemed worth doing. But this is medical dogma. This is what everybody was doing. And so we need to give the investigators who are asking the question about beta blockers post MI ate. Ton of credit to question something that is so ingrained in what we do, takes a lot of courage. I mean, prescribing beta blockers post Mi is this important quality metric that impacts hospital ratings and even physician reimbursement?

Dr. Shreya Trivedi: No, I had no idea.

Dr. Greg Katz: I used to get a report card about how many of my post mi patients were being prescribed beta blockers.

Dr. Shreya Trivedi: That is humbling.

Dr. Chris Kotanidis: Well, and all that brings us to REDUCE AMI – the first Randomized Control Trial in the space of beta blockers in a quarter century.

The REDUCE-AMI Trial

Dr. Chris Kotanidis: The REDUCE-AMI trial published in the New England Journal of Medicine in April of 2024 was an open label randomized control trial. It was conducted across 45 centers in Sweden, Estonia and New Zealand.

Dr. Clem Lee: And “REDUCE” for “Randomized Evaluation of Decreased Usage of Beta-blockers,” with the C and the E coming from the middle of the word beta blocker. Greg, I don’t know if this is my favorite cardiology trial acronym.

Dr. Greg Katz: On behalf of all of cardiology, we politely request you stop micromanaging our acronyms. But looking at these patients, their median age was 65 years old, 80% of them are men. About half had hypertension and one out of eight had a history of diabetes. Patients couldn’t be enrolled after STEMIs or NSTEMIs, and every single one went for coronary angiography and had obstructive coronary artery disease.

Dr. Shreya Trivedi: The investigators wanted to ask the question whether beta blocker therapy was beneficial for patients who had an acute MI and whose ejection fraction was 50% or greater.

Dr. Chris Kotanidis: And just to say it out loud, the reason why patients with a reduced ejection fraction were not included is because we know that there is a clear mortality benefit in treating systolic dysfunction with beta blockers.

Dr. Greg Katz: That restriction narrows down the patient population they were studying, and the trial enrolled about 5000 patients.

Dr. Shreya P. Trivedi: Okay, not to sound ungrateful here, but I’m surprised that a cardiology trial only included 5,000 patients. I’m so used to having cardiology trials have twice that number guessing. Some fancy stats were done, and the sample size calculation said, Okay, this was enough statistical power in this post, in my population, but still a little bit surprising.

Dr. Greg Katz: 5,000 patients, kind of impressive, just a lot of shade from the non cardiologist today. If this were a Lupus trial, there’d be like 50 patients, and it’d be a front page cardiologist set the standard so high, it’s not my fault that we spoil you with our evidence. And the patients here were randomly assigned to one of two groups. One group received beta blockers, specifically metoprolol or bisoprolol, and the other group received no beta blocker therapy, but they weren’t given a placebo. Treating physicians were encouraged to aim for a specific daily dose of about 100 mg of metoprolol succinate, or 5 mg of bisoprolol.

Dr. Shreya Trivedi: Huh? Why did they not use Carvedilol? I mean, carve it all had this big deal after CAPRICORN.

Dr. Chris Kotanidis: So yeah, REDUCE-AMI used beta-1 selective blockers, specifically metoprolol and bisoprolol for two reasons. First, these drugs are the most widely used ones in coronary artery disease, and also, practically speaking, Metoprolol and bisoprolol were just the commonly prescribed drugs in the countries involved in the trial.

Dr. Clem Lee: Okay? And I do want to point out a few major differences between this trial and some of the other trials we’ve covered on this podcast. First, this trial was open label, which means that patients and doctors both knew what they were getting. And second, there was no placebo group.

Dr. Greg Katz: And so those methodologic factors are really important, but when the outcomes in the study or new MI, which aren’t really subject to bias or the placebo effect, I really worry less about the lack of blinding or placebo control.

Dr. Clem Lee: Yeah, that’s fair. They also did something unique for the patients that we should point out for the patients who were on a beta blocker before enrollment, their beta blocker was tapered and stopped, they were assigned to the no beta blocker group, hmm.

Dr. Shreya Trivedi: All right, now, with all that groundwork on this trial, Chris, do you do the honors of telling us what the results were?

Dr. Chris Kotanidis: Sure? Do I get a drum roll? Well, the results were in a word neutral. So after a median of 3.5 years, the primary endpoint of death from any cause or a pneumococcal infarction occurred in 7.9% of the patients in the beta blocker group and 8.3% of patients in the no-beta-blocker group.

Dr. Shreya Trivedi: Okay, surprising. All right, so are we saying now that those hospital quality metrics need to be changed?

Dr. Greg Katz: That is not what we are telling you. That is what REDUCE-AMI is telling you.

Dr. Chris Kotanidis: Yeah, and to break down the composite primary endpoint, more incidence of death myocardial infarction is neutral. And when we look at secondary endpoints, death from cardiovascular causes also neutral. Hospitalization for afib, neutral. Hospitalization for heart failure, also neutral. So in the end, all of those numbers come out as totally neutral.

Dr. Greg Katz: So you would think that there’d be something in that composite for us to chew on, but there was nothing. And this is really provocative, this neutrality was across the board, and continued even to secondary outcomes where I was pretty sure beta blockers were gonna have an effect, like hospitalization for AFib or hospitalization for heart failure.

Dr. Shreya Trivedi: Yeah, that’s crazy. Beta blockers, we know to be important in helping with arrhythmia, so it’s yeah, very surprising here. So sounds like no benefit for beta blockers with those secondary efficacy endpoints too. How about safety endpoints? I mean, beta blockers are so. To raise for side effects.

Dr. Clem Lee: Yeah, totally. But the beta blockers were safe in this study, even if they weren’t efficacious, there was no difference in heart block, hypotension, syncope or new pacemaker indentations between the two groups. There was also no difference in hospitalizations for asthma or COPD, which is relevant here, since beta blockers also block beta two receptors on bronchial smooth muscles.

Dr. Greg Katz: And the neutrality here even extends to the subgroup analysis, and not to be a broken record, but for almost all studies, subgroup analysis are hypothesis generating, not hypothesis tested, but there was no signal that any particular group could benefit or harm from beta blocker treatment.

Dr. Shreya Trivedi: I wouldn’t be on journal club if we didn’t have Greg saying hypothesis generating, that hypothesis testing.

Dr. Chris Kotanidis: Okay? Well, to summarize, REDUCE-AMI showed no benefit on survival or heart attack risk with beta blocker therapy in patients who are post MI and have no LV Systolic Dysfunction.

Dr. Greg Katz: This is a wild result, and it is so different than what we were taught in med school and what we’re being judged on with these quality metrics, and frankly, what I’ve been teaching my residents for God knows how many years

Dr. Clem Lee: I’m sure your residents still think you’re a great teacher. But how sure are we about these results? You all know by now that I’m a huge cynic with a capital C.

Critique and Moving Forward

Dr. Chris Kotanidis: Okay, so, so in terms of how sure we are about the result. Clem, on the surface, we have an ultra trial here, but when you dig deeper, there was actually a lot of crossover.

Dr. Greg Katz: And to bring that point home, about one in five patients in the beta blocker group stopped taking the medication, and about one in seven assigned to the no-beta-blocker group started beta-blockers.

Dr. Shreya P. Trivedi: That’s a ton, but I guess that does mimic real life, right? Some patients don’t tolerate the medicine. Some patients need to start a new medicine after the initial treatment plan was decided on.

Dr. Greg Katz: In reality, that is absolutely true, but that crossover means that 20% of one group crossed over and 14% of the other group crossed over, and the primary outcome occurred 8% of the time. And those numbers leave me with a lot more uncertainty about what the right conclusions are to draw.

Dr. Chris Kotanidis: Yeah, and also remember that REDUCE-AMI was designed as an intention-to-treat trial. In intention to treat trials, patients are analyzed based on original assignments, so high crossover rates could potentially dilute the treatment effect.

Dr. Greg Katz: And even with every single one of these caveats, which are all important. This is still a vitally important trial that is going to change my practice. When I am looking at the results of REDUCE-AMI, I keep coming back to the fact that this is just not that sick a group of patients. I know this is a group of people that just had an MI, and for patients that is a life altering event, but from a cardiology perspective, they weren’t all that high risk. They had a normal ejection fraction, successful revascularization, average age of 65 very few of them had diabetes. And so this is a group of patients who, by any sort of risk evaluation you’d expect to do really well. So I’m interpreting the trial with this caveat, patients who aren’t that sick, and the addition of beta blockers isn’t going to move the needle for a group of people who you’re expecting.

Dr. Clem Lee: I think that’s a super important point, and really reinforces that we need to look at a population carefully when we’re examining a trial and older trials like CAPRICORN involve patients who are sicker, with larger MIs and more severe left ventricular dysfunction.

Dr. Chris Kotanidis: Okay, guys, I feel like we’ve been talking about all the trials a lot here, right? And maybe it’s worth shifting our focus to newer studies. The one that caught my eye and I think is worth contrasting with REDUCE-AMI is a base which was a beta blocker withdrawal study that was also published in NEJM around the same time.

Dr. Clem Lee: And as the acronym Guru, I will tell you that this stands for “Assessment of βeta Blocker Interruption After Uncomplicated mYocardial Infarction on Safety and Symptomatic Cardiac Events Requiring Hospitalization.” Like REDUCE, the trial acronym borrowed a letter from the middle of the word the Y is from the Y in myocardial infarction. I guess you could say that the Y came from the middle of the ABYSS.

Dr. Greg Katz: Your life much calmer and easier, if you just did not devote any brain space to cardiology trial acronyms, but abyss tested a different strategy than reduce this trial took beta blockers away from patients with stable ischemic heart disease and no recent MI who had been on them for a median of about 3 years.

Dr. Chris Kotanidis: And ABYSS studied a slightly sicker group of patients, including ejection fractions as low as 40% not 50% and what did they find? They actually found that withdrawing beta blockers increased hospitalizations.

Dr. Shreya P. Trivedi: Wait a minute with everything we’ve been discussing, first saying that beta blockers after a heart attack is what we should be doing, and then a meta analysis saying we don’t need it forever. And then abyss, suggesting that taking away beta blockers might actually increase hospitalizations. So does that mean we should just throw away REDUCE-AMI, it was a small study, 5,000 patients. I have so many questions here.

Dr. Greg Katz: Withdrawing a drug that’s stably in use is just different than starting something new. And so these are two different trials looking at. Two different questions in two different patient populations, and comparing them is comparing apples to oranges

Dr. Chris Kotanidis: That’s right, Greg, and I don’t think the results from ABYSS necessarily contradict the results from REDUCE AMI. ABYSS patients had lower EFS, and we know that beta blockers have benefited in this population.

Dr. Greg Katz: What I think we need to take away from these two trials is that understanding who the patient is matters a ton when you’re considering the risks and benefits of different treatment strategies. The sicker somebody is, the more aggressive it probably makes sense to be with their medical therapies. And when patients aren’t as sick, one of our jobs is to make sure that we don’t make things worse for them by over medicalizing their treatments.

Dr. Clem Lee: Yeah, totally agree. And the other take home point that I have is that clinical dogma really needs to be in question as the rest of standard of care evolves like, what should we clinicians be doing now?

Dr. Shreya P. Trivedi: Yeah, I think for me, my takeaway is that we shouldn’t reflexively prescribe a beta blocker to every patient after a heart attack. And I think for patients who have preserved ejection fraction, who don’t have any other indication for a beta blocker, like they don’t have to be on a beta blocker for rate control in AFib or angina. It seems like the benefit of the beta blocker is less here.

Dr. Clem Lee: Yeah, this is a huge shift in how we think about beta blockers. I liked how the editorialist Dr. Yaron Brook put it, and by the way, he’s the PI of REDUCE-Ami. I thought beta blockers are, quote, approaching retirement. I just thought that was like an elegant way of describing something that had a good run, but we might think about phasing out, at least for a subset of patients.

Dr. Shreya P. Trivedi: Yeah, a big retirement party.

Dr. Greg Katz: I’m also going to add one additional cynical take, which is that this is another case of good hearts law rearing its head again about the concept of paying for quality in medicine. Good heart’s law comes from economics, and it says that “when a measure becomes a target, it ceases to be a good measure.” And this is applicable because of the way that beta blocker prescriptions post mi are considered an important quality metric for hospitals and for doctors. Maybe that was the case in a prior era, but I think it’s really hard to make an argument that we should be incentivizing doctors through rankings to prescribe something with a questionable benefit in the modern age. And if our quality guidelines and our quality metrics do not evolve as quickly as the evidence base does. We have this gigantic metricized problem on our hands.

Dr. Chris Kotanidis: But also, we all know how much cardiologists love doing trials. This will not be the last word on the topic. We have ongoing trials like SMART-DECISION, BET-AMI, and DANBLOCK that are pretty much asking very similar questions and are projected to recruit even more patients.

Dr. Greg Katz: And I’m really looking forward to dissecting those trials, and probably less looking forward to hearing Clem’s critiques about their acronyms. Hey…

Dr. Shreya P. Trivedi: There’s a lot of like, cardiology bound people who are just like thinking about acronyms all the time. But yes, the story will continue to evolve.

Dr. Greg Katz: And something that we’ve said on this podcast before is that you shouldn’t let one single trial completely sway your practice, unless you are more gullible than you should be. And so we have all of these smart investigators around to thank that they asked this important question about beta blockers post MI, and pretty soon, we’re going to have a lot more data so we’re going to be able to make decisions for our patients with an even greater degree of precision.

Dr. Shreya P. Trivedi: And change quality guidelines, maybe, hopefully. And then, before we wrap up, a little behind the scenes, we went back and forth about a story that Greg shared with us in one of our sessions. It was actually after the REDUCE-AMI trial had come out, and this outcome for this patient kept him up at night, and he’s thought about it over 100 times. And my vote was like, yes, let’s have it on air. For me, it really hammered home some of the gaps when you try to translate the evidence to the patient in front of you. So stay tuned after the quick credits, if you want to hear the story, I think it’ll certainly give even more food for thought to this topic.

Dr. Greg Katz: And with that, we wrap up this episode. If you got any value from this podcast, our ask is that you share it with at least one other colleague who might also find this helpful.

Dr. Shreya P. Trivedi: Thank you to our peer reviewer, Dr. Jane Leopold. Thank you to Dr, Jim and Wong for the accompanying graphics.

Dr. Clem Lee: And if you have any feedback or suggestions, please email us at Hello at core, I am podcast.com opinions express our own and don’t represent affiliated institutions.

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